The present invention relates to a process for grafting acrylamide onto an polymeric substrate. The invention also relates to a method for improved biocompatibility of polymeric surfaces.
The grafting of a polymer to a polymeric substrate depends on the creation of active sites on the substrate. In general, there are three approaches to creating these active sites so that graft polymerization can occur: chain-transfer activation, radiation or photochemical activation, and chemical activation. Both chain transfer and chemical activation can be applied to either radical or ionic graft polymerization methods.
Activation grafting is the creation of active sites on the substrate by the absorption of radiant energy. Gamma radiation, ultraviolet radiation, corona discharge, radio frequency glow discharge, electron beam radiation or other high energy radiation can be used as the energy source. The activation can be conducted as preirradiation of the polymeric substrate or as mutual irradiation of the polymeric substrate and the monomer to be grafted. By either method, the rate and efficiency of the initiation is dependent upon the type of radiation, the radiation dose (total energy absorbed), the dose rate (rate at which energy is absorbed), and the radiation sensitivity of materials involved. For an example of this method, in U.S. Pat. No. 3,826,678 issued to Hoffman et al., a polymeric substrate is subjected to radiation and thereafter is exposed to a deaerated monomer solution which covalently bonds the monomer to the irradiated surface to produce a surface with improved biocompatibility. Also, for example, Ikada ("Surface Modification of Silicones for Tissue Adhesion" Biomaterials and Clinical Applications, Elsevier Science Publishers B.V., Amsterdam, 1987) uses corona discharge to activate surfaces followed by grafting by application of a deaerated aqueous solution of monomers. Also, for example, in U.S. Pat. No. 5,080,924 issued to Kamel et al., radio frequency glow discharge is used to treat a polymeric surface followed by contacting the treated surface with compounds such as acrylic acid in vapor phase to graft pendant carboxyl or amine groups to the polymeric substrate, thereby improving its biocompatibility. However, the effectiveness of radiation grafting to impart improved biocompatibility to some substrates can be quite limited. Silicone-based polymers, polyolefins and fluoropolymers have not proved to be as good substrates for activation grafting with radiant energy as acrylic and styrene-based polymers. Also, the need to eliminate oxygen from any monomer solution used for the grafting process can add greatly to the expense and difficulty of the process.
Chemical grafting is the term applied to grafting reactions involving preformed labile groups either on the backbone or on pendant groups of the substrate, and can be used in the preparation of graft polymers by either free radical or ionic methods. In particular, a free radical reaction mechanism in aqueous solution can be used in which water soluble ethylenically unsaturated monomeric material is grafted onto a substrate, with the free radicals formed on the substrate by an oxidizing metal capable of being reduced by the substrate to a lower valency state (for instance ceric ion). Ceric ion grafting is applicable to a large variety of polymeric backbones, both natural and synthetic. Ceric ion initiated graft polymerization has also been utilized in conjunction with a large number of hydroxyl-, thiol-, and amine- containing polymeric substrates. Ceric ion grafting has been used to improve the biocompatibility of urethane polymers used in blood compatible devices such as artificial hearts, ventricular assist devices and extra-aortic balloons. Again, however, the effectiveness of ceric ion grafting to impart biocompatibility to substrates such as silicone-based polymers, polyolefins and fluoropolymers can be quite limited. And again, the need to eliminate oxygen from any monomer solution used for the grafting process can add greatly to the expense and difficulty of the process.
Ceric ion grafting is known to work best when the monomer does not have a tendency to precipitate with the ceric ion, for instance when used with acrylamide, rather than with monomers which include anionic material since these monomers tend to precipitate in the presence of ceric ion.
Ultraviolet light has also been used with ceric ion grafting of acrylamide to polymeric substrates. In Chen et al, "Graft Copolymerization of Acrylamide onto the UV-Ray Irradiated Film of Polyester-Polyether", Journal of Polymer Science, 6(1):14-19, 1988, both sides of a PBT-PTMG film were exposed to UV light followed by immersion of the film into an aqueous solution of acrylamide and the addition of ceric ammonium nitrate. However, such grafting methods are not surface limited in that the amount of UV light needed to effect the grafting reaction also adversely affects the bulk properties of the substrate material. The grafting technique can also produce an unstable graft with small oligomers that wash off with gentile rubbing. These deficiencies are especially undesirable for grafted materials to be used in implantable medical devices since contact with tissue and body fluids could rapidly remove the grafted material.
In order to provide materials with improved biocompatibility and reduced tendency to cause blood coagulation, it is desirable to prevent the occurrence of physicochemical interactions between polymeric substrates and factors which control processes such as blood and tissue cell reaction, thrombosis, thromboembolization, infection and inflammatory response. Cells in living organisms have chemical constituents on their cell membranes that regulate interactions with blood and other tissues. Highly hydrophilic and/or mobile polymer chains on the surface of a polymeric substrate could provide a surface that limits interactions between living tissues and the substrate. Therefore, graft polymerization utilizing monomers such as 2-hydroxyethyl methacrylate and acrylamide have been proposed. Also of interest for improved biocompatiblity is the adsorption or attachment of proteins or other bioaffecting molecules to the polymeric substrate by which the substrate will either be provided with a passivating layer or with a layer which is physiologically active.
Since the ideal blood-surface interface has long been considered to be the naturally occurring human endothelium, research has also focused on endothelialization procedures. For example, pretreatment of prosthetic vascular graft material with fibronectin, collagen or blood plasma has been found to produce substantial increases in adherence of endothelial cells to the graft. However, substrates such as silicones and fluoropolymers do not allow protein coatings to tightly adhere to their surfaces. One proposed solution to this problem is set forth in U.S. Pat. No. 5,055,316 issued to Hoffman et al. in which the substrate is exposed to a polymerizable gas in the presence of a plasma gas discharge and is subsequently exposed to a protein solution to cause the protein to bind tightly to the substrate.
It is therefore an object of the present invention to provide a method for grafting acrylamide onto a polymeric substrate without the need for a deaerated monomer solution.
It is also an object of the present invention to provide a method for grafting acrylamide onto difficult to graft substrates such as silicones or fluoropolymers.
It is also an object of the present invention to provide a method for grafting acrylamide which preserves the bulk properties of the substrate polymer.
It is also an object of the present invention to provide an acrylamide grafted surface with improved stability and resistance to mechanical wear.
It is also an object of the present invention to provide a grafted surface with improved biocompatibility that may be used for materials to be implanted in humans and animals.
It is also an object of the present invention to provide a grafted surface suitable for attachment of biomolecules and endothelial cells.